Acute Lung Injury (ALI) and lung ischemia/reperfusion are devastating prevalent acute clinical syndromes that have no effective pharmacotherapy. The derangement of endothelial monolayer in the pulmonary vasculature is the common key component of their pathogenesis. In particular, reactive oxygen species (ROS) produced in endothelial caveolar endosomes mediate harmful pro- inflammatory abnormalities in these cells, unleashing the vicious cicle of mutual propagation of inflammation, oxidative stress and tissue injury. We have designed nanocarriers (NC) for targeted endothelial delivery of antioxidant and anti-inflammatory agents, which exerted protective effects in animal models of ALI and I/R unmatched by untargeted counterparts. Results of pilot studies indicate that: i) antioxidant delivery in caveolar endosomes further boosts the protective effect; ii) antibody- targeted elastic nanogel carriers (Ab/NG) accumulate in the pulmonary caveoli despite being larger than caveolar entrance; and, iii) inflammation boosts caveolar targeting of large rigid Ab/NC that otherwise do not accumulate in the lungs of nave mice. We will use Ab/NG and Ab/NC targeted to caveolar target PV1 versus previously characterized non-caveolar target PECAM, to define mechanism of the endothelial targeting of antioxidants, characterize its benefit-risk ratio and enable its clinical translation by pursuing the following Specific Aims: 1) Control targeting to caveolae in normal and pathologically altered endothelial cells; 2) Characterize benefit/risk ratio of Ab/NG and Ab/NC in clinically relevant animal models using clinically relevant readouts; and, 3) Re-engineer affinity moieties of Ab/NG and Ab/NC in a molecular format useful in human patients and test their endothelial targeting and activity in perfused and ventilated isolated human lungs. We posit that carriers targeted to caveolar endosomes will be unrivaled in mitigating inflammatory abnormalities typical of ALI and I/R. Nevertheless, Aims 2 & 3 are not dependent on Aim 1, since they will for the first time determine benefit/risk ratio of PECAM-targeted carriers with already established superiority to untargeted counterparts. This study will enable clinical translation of a promising approach for ALI and I/R treatment.